Peter Baluk and Donald M. McDonald Department of Anatomy, Cardiovascular Research Institute, and UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143-0452, USA Correspondence: peter.balukucsf.edu

Button-like junctions are discontinuous contacts at the border of oak-leaf-shaped endothelial cells of initial lymphatic vessels. These junctions are distinctively different from continuous zipper-like junctions that create the endothelial barrier in collecting lymphatics and blood vessels. Button junctions are point contacts, spaced about 3 µm apart, that border valve-like openings where fluid and immune cells enter lymphatics. In intestinal villi, openings between button junctions in lacteals also serve as entry routes for chylomicrons. Like zipper junctions that join endothelial cells, buttons consist of adherens junction proteins (VE-cadherin) and tight junction proteins (claudin-5, occludin, and others). Buttons in lymphatics form from zipper junctions during embryonic development, can convert into zippers in disease or after experimental genetic or pharmacological manipulation, and can revert back to buttons with treatment. Multiple signaling pathways and local microenvironmental factors have been found to contribute to button junction plasticity and could serve as therapeutic targets in pathological conditions ranging from pulmonary edema to obesity.